1. Field of the Invention
The invention concerns the simulation, by a programmed, general purpose digital computer, of chemicals that have biological functions, and more specifically, concerns computer-implemented simulation of such chemicals based upon their synthesis and their assayed biological activity.
2. Description of the Related Art
Currently, there is no method or means for simulating the relationship between a chemical produced in a laboratory, a biological function of the chemical as experimentally measured in an assay, and the outcome of the experiment where the chemical is assayed. The ability to simulate such an experiment could vastly improve prediction of the outcome, enabling the use of the information developed in simulation to better identify and develop chemicals that will produce desired effects on selected biological receptors.
Currently, chemicals having biologically efficacious functions are synthesized from chemical libraries that contain huge numbers of chemicals. Based upon clinical structures, experience, intuition, or strictly random sampling, sets of chemicals are selected from a chemical library, and they are combined in chemical reactions subject to known reaction conditions to produce product chemicals. The biological function of the product chemicals is measured experimentally in an assay procedure, with the degree to which a product chemical achieves a desired biological function being indicated by a numerical value. After synthesis, thousands, or tens of thousands, of product chemicals may be assayed, with the assay results being determined and ranked by known means.
These large numbers of product chemicals are synthesized in order to discover one, or a few product chemicals that react with a protein to produce a desired effect, such as one that would inhibit or impair the progress of a disease. Assume that the disease is inhibited by attachment of an enzyme to a known location on the protein. The known location is called a "receptor site". Assume that attachment of a product chemical to the protein at receptor sites of interest inhibits enzyme attachment, thereby strongly indicating that the product chemical would also inhibit the progress of the disease. In this regard, attachment of the product chemical to a receptor site of interest would mimic the therapeutic effect of a (possibly scarce) naturally occurring compound. In this case, the product chemical would comprise a synthetic substitute for the scarce compound.
In any event, an assay may be conducted to determine whether, and to what extent, the product chemical binds to receptor sites of interest by coating a well or a container with the protein and then washing the protein with a solution containing the product chemical. Excess solution is emptied from the coated well and the compound for which a block, or substitute, is sought is "tagged" with another compound and, so tagged, is brought, in solution, against the protein. The extent to which the product chemical binds is evaluated by introducing another chemical that "develops" the tagging compound. In this regard, development activates the tagging compound in the sense that the tagging compound shows a certain color. Introduction of the protein to a spectrophotometer enables the detection of chemical activity by the measurement of color. Thus, if the tagged compound is not blocked, it will bind to the protein at the receptor sites and its presence will be indicated by the color of the tagging compound. If altogether blocked, the color of the tagging compound will not be detected at all or, if partially blocked, a smaller amount of the color will be detected.
Color-based assay techniques are well known, and apparatus are available to conduct photoassay of a great number of separate reactions. One such device is a spectrophotometer available from Molecular Devices that automatically conducts photoassay of a plurality of reactions in an array of reaction wells. Such a spectrophotometer can be coupled to a programmed, general purpose digital computer to process the results of an M.times.N array of reaction wells. For example, a MacIntosh brand computer available from the Apple Corporation, running the SOFTMX application program, also available from Molecular Devices, provides an output that presents photoassay results of a plurality of normalized assay result values, referenced to maximum and minimum values of a tagging color.
While the synthesis/assay process is well known and widely used, it is time-consuming and very manpower-intensive. To the extent that the process is iterative, because it is manually performed, desirable results emerge slowly, and patterns of desirable activity by product chemicals may be difficult to detect.
Manifestly, automated means and methods for simulating the direct synthesis/assay procedure have the potential of vastly increasing the speed of the process and quickly identifying patterns or trends of desirable results. However, to date only the evaluation phase of the assay step has been automated, and that only to a rudimentary degree. As yet, no effective mode of simulating the synthesis/assay process has emerged. Attempts have been made to create simulation models based upon molecular structure of product chemicals. However, such attempts have yet to find an effective model that links how a chemical is made and what its structure is, once synthesized. Accordingly, a manifest need exists for a method and means that simulate product chemicals in a way that directly reveals how they may be made and what their biological functions are.